EP0168965B1 - 4(5)-substituted imidazoles - Google Patents

4(5)-substituted imidazoles Download PDF

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Publication number
EP0168965B1
EP0168965B1 EP85304239A EP85304239A EP0168965B1 EP 0168965 B1 EP0168965 B1 EP 0168965B1 EP 85304239 A EP85304239 A EP 85304239A EP 85304239 A EP85304239 A EP 85304239A EP 0168965 B1 EP0168965 B1 EP 0168965B1
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EP
European Patent Office
Prior art keywords
formula
compound
imidazole
compounds
produce
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired
Application number
EP85304239A
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German (de)
English (en)
French (fr)
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EP0168965A1 (en
Inventor
Kenneth Steven Hirsch
Harold Mellon Taylor
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Eli Lilly and Co
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Eli Lilly and Co
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Publication date
Application filed by Eli Lilly and Co filed Critical Eli Lilly and Co
Priority to AT85304239T priority Critical patent/ATE38516T1/de
Publication of EP0168965A1 publication Critical patent/EP0168965A1/en
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Publication of EP0168965B1 publication Critical patent/EP0168965B1/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • This invention provides imidazole derivatives of the formula I wherein
  • the compounds of the above formula are useful in the treatment and prevention of estrogen-dependent diseases, especially breast cancer, in mammals.
  • Estrogens are synthesized from androgenic steroids. In the biosynthetic pathway for estrogen formation, aromatization is an essential step. It is generally believed that if the aromatase enzyme could be effectively inhibited, a useful treatment for estrogen dependent disorders could be obtained [see Cancer Research, Vol. 42, Suppl. 8:3261s (1982)].
  • aromatase inhibitors include breast cancer, endometriosis, polycystic ovarian disease, benign breast disease, and endometrial cancer.
  • a beneficial effect of antiestrogens in the treatment of breast cancer has been well established [see Br. J. Cancer, 25, 270 (1971)].
  • Two of the known aromatase inhibitors, testolactone and aminoglutethimide, have shown a beneficial effect in treatment of breast cancer. See Cancer Research, supra.
  • Endometriosis is characterized by an abnormal proliferation of the endometrium of the uterus. Since the endometrium is dependent on estradiol for its growth, an inhibitor of estrogen production should stop the progression of the disease.
  • Benign breast disease or often called fibrocystic breast disease, appears to be dependent on ovarian steroids. See Cancer, 49, 2534 (1982). Aromatase inhibitors have not been tried in this disease, but antiestrogens seem to be of benefit. See Obstet. Gynecol.,54, 80 (1979).
  • Polycystic ovarian disease is one of the most common causes of infertility in women. The disease appears to result from an abnormality in steroid metabolism, and the major form of therapy in this disease is the antiestrogen, clomiphene. See Clin. Endocrinol., 12, 177 (1980).
  • the invention also provides pharmaceutical formulations comprising one or more of the compounds of the above formula in combination with a suitable pharmaceutical carrier, diluent, or excipient therefor.
  • a suitable pharmaceutical carrier diluent, or excipient therefor.
  • the formulations provided by this invention are particularly useful in treating mammals suffering from estrogen-dependent diseases such as breast cancer.
  • the pharmaceutically acceptable acid addition salts used in this invention include salts derived from inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydriodic acid or phosphorous acid, as well as salts derived from organic acids such as aliphatic mono- and di-carboxylic acids, phenyl-substituted alkanoic acids, hydroxy-alkanoic and -alkanedioic acids, aromatic acids, aliphatic or aromatic sulfonic acids.
  • inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydriodic acid or phosphorous acid
  • organic acids such as aliphatic mono- and di-carboxylic acids, phenyl-substituted alkanoic acids, hydroxy-alkanoic and -alkanedioic acids, aromatic acids, aliphatic or aromatic sulf
  • Typical pharmaceutically acceptable salts thus include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, fluoride, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, mandelate, butyne-1,4-dioate, hexyne-1,6- dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, terephthalate, benzenesulfonate, toluenesulf
  • the compounds of this invention can be prepared by methods described in the art.
  • the compounds employed in this invention are generically taught in British Patent Application GB 2,101,114; however, none of the presently claimed compounds are specifically disclosed.
  • the presently claimed compounds can be prepared by the methods described in the British Application.
  • the following schemes summarize general methods to prepare the compounds of formula I wherein Q is hydrogen or hydroxy: wherein X is chloro or bromo.
  • imidazole (II) is treated with a strong alkali metal base, such as sodium hydride or n-butyllithium, in a non-reactive solvent, such as dimethylformamide or tetrahydrofuran.
  • a strong alkali metal base such as sodium hydride or n-butyllithium
  • a non-reactive solvent such as dimethylformamide or tetrahydrofuran.
  • This reaction provides a mixture of the 1-, 2- and 4-alkali metal derivatives of imidazole which is then reacted with the corresponding methyl halide or ketone derivative.
  • the reaction is generally complete within 2-24 hours when the reaction is allowed to proceed at temperatures from about 0-100°C.
  • the reaction provides the corresponding derivatives of formula I wherein Q is hydrogen or hydroxy, together with the undesirable 1- and 2-substituted imidazoles.
  • the isomeric materials may be isolated by known procedures, such as chromatography or crystallization.
  • the carbinol derivatives (Q is hydroxy) can also be prepared from the hydrogen compound by treating a basic solution of the hydrogen compound with air or oxygen. Conversely, the carbinol derivative may be transformed to the hydrogen compound following the procedure of U.S. Patent No. 2,727,895.
  • the invention provides a process for preparing a compound of the formula I wherein
  • a Grignard reagent was prepared from 4.7 g of magnesium turnings, a catalytic amount (four drops) of 1,2-dibromomethane in 2 ml of diethyl ether, and 25.0 g of 4-bromochlorobenzene in 100 ml of tetrahydrofuran. After stirring for approximately two hours, 5.0 g of methyl 4-imidazolecarboxylate were added as a solution in 50 ml of tetrahydrofuran. The mixture was heated at reflux for one hour. The tetrahydrofuran was removed by evaporation and the remaining mixture was poured into an iced ammonium chloride solution and extracted with ethyl acetate.
  • the compounds of this invention are useful in preventing or therapeutically treating estrogen-dependent diseases, including breast cancer, in mammals by virtue of their ability to inhibit the enzyme aromatase.
  • Their ability to inhibit aromatase was demonstrated by employing a modification of the isolated rat ovarian microsome method of Brodie et al. in J. Steroid Biochem., 7, 787 (1976). In this test system, ovarian microsomes are obtained from rats treated with pregnant mares serum gonadotropin. Test compounds are added to reaction vials containing 0.1 ⁇ M 4-androstene-3,17-dione, 100,000 dpm 1,2[ 3 H]-androstenedione, the microsomes and a NADPH generating system.
  • the concentrations of the inhibitors tested ranged between 0.005 and 10 um.
  • aromatization of androstenedione results in the production of [ 3 H]-H 2 0 which is isolated by extracting the samples with chloroform and treating the aqueous phase with charcoal to remove the free steroid.
  • Samples are counted in a liquid scintillation spectrometer and the percent inhibition determined by comparing the results with control samples incubated without inhibitor. Potency is determined based on the concentration of inhibitor in ⁇ M required to produce a 50% inhibition of enzyme activity (EC 50 ) when the concentration of substrate (androstenedione) is 0.1 ⁇ M.
  • the EC 50 's of certain of the compounds of the above formula are summarized in Table 1.
  • the compounds of this invention are able to inhibit the synthesis of estrogens in mammals, thereby making the compounds useful in the treatment of estrogen-dependent diseases, such as breast cancer. This activity was demonstrated in the following in vivo test system.
  • Immature female Wistar rats (45-55 grams) were divided into control and test groups of 4-5 animals each. Test compounds were administered for seven days daily by gavage in corn oil. Control animals received corn oil without the test compound. Beginning on the fourth day of the test, all animals treated with the test compound and one half of the control animals were given a subcutaneous injection of 1.0 mg of testosterone propionate in corn oil. The remaining control animals received only an equivalent volume of corn oil. On the seventh day of the test, rats treated with testosterone propionate were injected subcutaneously with 100 ⁇ Ci of [ 3 H]-testosterone in 50 pl of 3:1 (v/v) saline-ethanol.
  • the animals were killed by decapitation. Uteri were isolated, trimmed of extraneous connective tissue, and weighed. As summarized in Table 2 below, the corn oil treated animals exhibited low uterine weight and represent unstimulated or negative controls. In the control animals treated with testosterone propionate, estrogens produced by aromatization stimulated the uterus resulting in an increase in weight. Compounds which inhibit aromatization produced urerine weights significantly lower than those of the testosterone treated controls.
  • Ovaries from rats treated with [ 3 H]-testosterone were excised, cleaned of extraneous tissue, and homogenized in 2.5 ml of a 1.0 mM potassium phosphate buffer containing 3.0 mM MgC1 2 -6H 2 0, 320 mM sucrose, and 0.25% Triton X-100 (polyethylene glycol p-isooctyl phenyl ether, Rohm and Haas) at pH 6.5.
  • Triton X-100 polyethylene glycol p-isooctyl phenyl ether, Rohm and Haas
  • the ovarian steroids were extracted with 1.5 ml of 9:1 (v/v) toluene/ethanol to which had been added 25 to 100 mcg each of unlabelled estradiol, estriol, and estrone, and approximately 1000 dpm of [ 14 C]-estradiol.
  • the samples were vortexed, centrifuged at 500 x g for 10 minutes, and the organic phase was transferred to a conical vial. Two additional extractions were performed on the residue in the same way.
  • the pooled organic extracts were evaporated for subsequent thin-layer chromatography.
  • Ovarian proteins were precipitated by the addition of 5.0 ml of ethanol to the remaining aqueous phase. After an overnight incubation at 4°C, the samples were centrifuged at 1500 x g for 10 minutes. The supernatant was discarded and the pellet was dissolved in 0.3 N potassium hydroxide. Protein was determined according to the method of Bradford, Analytical Biochemistry, 72, 248 (1976).
  • the compounds of this invention may be administered by any number of routes, including the oral, subcutaneous, intramuscular, intravenous, transdermal, and rectal routes.
  • the compounds are usually employed in the form of pharmaceutical compositions.
  • Such compositions are prepared in a manner well known in the pharmaceutical art and comprise from about 1 to about 95 percent by weight of at least one active compound of the formula I.
  • compositions comprise as active ingredient a compound of the above formula associated with a pharmaceutically acceptable carrier.
  • the active ingredient will usually be mixed with a carrier, or diluted by a carrier, or enclosed within a carrier which may be in the form of a capsule, sachet, paper or other container.
  • the carrier serves as a diluent, it may be a solid, semi-solid or liquid material which acts as a vehicle, excipient or medium for the active ingredient.
  • the composition can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, emulsions, solutions, syrups, suspensions, aerosols (as a solid or in a liquid medium), ointments containing for example up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.
  • suitable carriers, excipients, and diluents include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, tragacanth, gelatin, syrup, methyl cellulose, methyl- and propylhydroxybenzoates, talc, magnesium stearate, water, and mineral oil.
  • the formulations can additionally include lubricating agents, wetting agents, emulsifying and suspending agents, preserving agents, sweetening agents or flavoring agents.
  • the compositions may be formulated so as to provide quick, sustained, or delayed release of the active ingredient after administration to the patient by employing procedures well known in the art.
  • a compound of this invention can be admixed with carriers and diluents molded into tablets or enclosed in gelatin capsules.
  • the mixtures can alternatively be dissolved in liquids such as ten percent aqueous glucose solution, isotonic saline or sterile water, and administered intravenously or by injection.
  • Such solutions can, if desired, be lyophilized and stored in a sterile ampoule ready for reconstitution by the addition of sterile water for ready intramuscular injection.
  • compositions are preferably formulated in a unit dosage form, each dosage containing from about 1 to about 500 mg, more usually about 5 to about 300 mg, of the active ingredient.
  • unit dosage form refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with the required pharmaceutical carrier.
  • the active compounds are effective over a wide dosage range.
  • dosages per day will normally fall within the range of about 0.05 to about 300 mg/kg of body weight.
  • the range of about 0.1 to about 50 mg/kg, in single or divided doses is preferred.
  • the amount of the compound actually administered will be determined by a physician, in the light of the relevant circumstances including the condition to be treated, the choice of compound to be administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the chosen route of administration, and therefore the above dosage ranges are not intended to limit the scope of the invention in any way.
  • Hard gelatin capsules are prepared using the following ingredients:
  • the above ingredients are mixed and filled into hard gelatin capsules in 460 mg quantities.
  • Capsules each containing 20 mg of active ingredient are made as follows:
  • the active ingredient, cellulose, starch and magnesium stearate are blended, passed through a No. 45 mesh U.S. sieve and filled into hard gelatin capsules in 200 mg quantities.
  • Capsules each containing 100 mg of active ingredient are made as follows:
  • rablets each containing 10 mg of active ingredient are made up as follows:
  • the active ingredient, starch and cellulose are passed through a No. 45 mesh U.S. sieve and mixed thoroughly.
  • the solution of polyvinylpyrrolidone is mixed with the resultant powders which are then passed through a No. 14 mesh U.S. sieve.
  • the granules so produced are dried at 50-60°C and passed through a No. 18 mesh U.S. sieve.
  • the sodium carboxymethyl starch, magnesium stearate and talc, previously passed through a No. 60 mesh U.S. sieve, are then added to the granules which, after mixing, are compressed on a tablet machine to yield tablets each weighing 100 mg.
  • a tablet formula is prepared using the ingredients below:
  • the components are blended and compressed to form tablets each weighing 665 mg.
  • Suppositories each containing 25 mg of active ingredient are made as follows:
  • the active ingredient is passed through a No. 60 mesh U.S. sieve and suspended in the saturated fatty acid glycerides previously melted using the minimum heat necessary. The mixture is then poured into a suppository mold of nominal 2 g capacity and allowed to cool.
  • the active ingredient is passed through a No. 45 mesh U.S. sieve and mixed with the sodium carboxymethylcellulose and syrup to form a smooth paste.
  • the benzoic acid solution, flavor and color is diluted with some of the water and added, with stirring. Sufficient water is then added to produce the required volume.
  • An aerosol solution is prepared containing the following components:
  • the active compound is mixed with ethanol and the mixture added to a portion of the propellant 22, cooled to -30°C and transferred to a filling device.
  • the required amount is then fed to a stainless steel container and diluted further with the remaining amount of propellant.
  • the valve units are then fitted to the container.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Luminescent Compositions (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Macromolecular Compounds Obtained By Forming Nitrogen-Containing Linkages In General (AREA)
  • Epoxy Resins (AREA)
  • Steroid Compounds (AREA)
EP85304239A 1984-06-18 1985-06-14 4(5)-substituted imidazoles Expired EP0168965B1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AT85304239T ATE38516T1 (de) 1984-06-18 1985-06-14 4(5)-substituierte imidazole.

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US62159784A 1984-06-18 1984-06-18
US621597 2000-07-21

Publications (2)

Publication Number Publication Date
EP0168965A1 EP0168965A1 (en) 1986-01-22
EP0168965B1 true EP0168965B1 (en) 1988-11-09

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ID=24490833

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EP85304239A Expired EP0168965B1 (en) 1984-06-18 1985-06-14 4(5)-substituted imidazoles

Country Status (17)

Country Link
EP (1) EP0168965B1 (da)
JP (1) JPS6112667A (da)
KR (1) KR860000267A (da)
AT (1) ATE38516T1 (da)
AU (1) AU4373785A (da)
CA (1) CA1238640A (da)
DE (1) DE3566115D1 (da)
DK (1) DK269785A (da)
ES (1) ES8704464A1 (da)
GR (1) GR851423B (da)
HU (1) HU195190B (da)
IL (1) IL75487A0 (da)
NZ (1) NZ212389A (da)
PH (1) PH21210A (da)
PT (1) PT80628B (da)
SU (1) SU1398774A3 (da)
ZA (1) ZA854400B (da)

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
LU85747A1 (fr) * 1985-01-28 1986-08-04 Continental Pharma Derives d'imidazole leur preparation et utilisation ainsi que les compositions pharmaceutiques contenant des derives
GB2229719B (en) * 1989-03-30 1992-04-29 Farmos Oy Novel aromatase inhibiting 4(5)-imidazoles
PE20010781A1 (es) 1999-10-22 2001-08-08 Takeda Chemical Industries Ltd Compuestos 1-(1h-imidazol-4-il)-1-(naftil-2-sustituido)etanol, su produccion y utilizacion
EP2250153B1 (en) * 2008-01-18 2013-06-19 Allergan, Inc. Substituted-aryl-(imidazole)-methyl)-phenyl compounds as subtype selective modulators of alpha 2b and/or alpha 2c adrenergic receptors

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2946804A (en) * 1958-12-29 1960-07-26 Abbott Lab (5-methyl-4-imidazolyl)-diphenyl carbinol salts and lower alkyl quaternaries
GB2101114B (en) * 1981-07-10 1985-05-22 Farmos Group Ltd Substituted imidazole derivatives and their preparation and use

Also Published As

Publication number Publication date
ES544133A0 (es) 1987-04-01
CA1238640A (en) 1988-06-28
KR860000267A (ko) 1986-01-27
IL75487A0 (en) 1985-10-31
JPS6112667A (ja) 1986-01-21
DK269785D0 (da) 1985-06-14
EP0168965A1 (en) 1986-01-22
DK269785A (da) 1985-12-19
ES8704464A1 (es) 1987-04-01
DE3566115D1 (en) 1988-12-15
PT80628B (en) 1987-04-28
ATE38516T1 (de) 1988-11-15
HU195190B (en) 1988-04-28
PH21210A (en) 1987-08-19
ZA854400B (en) 1987-02-25
AU4373785A (en) 1986-01-02
SU1398774A3 (ru) 1988-05-23
GR851423B (da) 1985-11-25
NZ212389A (en) 1987-11-27
PT80628A (en) 1985-07-01
HUT38320A (en) 1986-05-28

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